Kalirin, a multi-domain protein with two guanine nucleotide exchange domains, and a cytosolic interactor with peptidyl glycine alpha-amidating monooxygenase (PAM), has been found in various regions of the CNS. Specifically it is found in the striatum and nucleus accumbens, areas that are involved in drug addiction and reward mechanisms. Kalirin-12 differs from the other two major isoforms by being highly expressed during early postnatal development, which is a crucial time for neuronal wiring, and having a distinctly different localization pattern in adult neurons. This isoform differs from Kalirin-7 and- 9 in its carboxyl terminal, with Kalirin-12 having a unique kinase-like domain. No function has been assigned to the kinase domain of Kalirin-12. Kinase domains are known to be involved in signaling pathways and altered kinase activity is implicated in many diseases. Based on my preliminary data, Kalirin-kinase appears to have independent functionality. When the kinase domain is expressed in striatal neurons, the cellular morphology is altered. The overall goal of this proposal is to investigate the role of the kinase domain of Kalirin. More specifically, the projects proposed will determine whether the kinase domain is involved in routing the full-length Kalirin-12 molecule to the cell soma, what it does to a cell, and, if it is an active kinase, its specific substrates.